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Background An infection-immune association of periodontal disease with rheumatoid arthritis has been suggested. This study aimed to investigate the effect of pre-existing periodontitis on the development and the immune/inflammatory response of pristane-induced arthritis. Methods We investigated the effect of periodontitis induced by ligature placement and Porphyromonas gingivalis ( P. gingivalis ) infection, in combination with Fusobacterium nucleatum to promote its colonization, on the development of pristane-induced arthritis (PIA) in rats (Dark Agouti). Disease progression and severity of periodontitis and arthritis was monitored using clinical assessment, micro-computed tomography (micro-CT)/intraoral radiographs, antibody response, the inflammatory markers such as α-1-acid glycoprotein (α-1-AGP) and c-reactive protein (CRP) as well as cytokine multiplex profiling at different time intervals after induction. Results Experimentally induced periodontitis manifested clinically (P < 0.05) prior to pristane injection and progressed steadily until the end of experiments (15 weeks), as compared to the non-ligated arthritis group. Injection of pristane 8 weeks after periodontitis-induction led to severe arthritis in all rats demonstrating that the severity of arthritis was not affected by the pre-existence of periodontitis. Endpoint analysis showed that 89% of the periodontitis-affected animals were positive for antibodies against arginine gingipain B and furthermore, the plasma antibody levels to a citrullinated P. gingivalis peptidylarginine deiminase (PPAD) peptide (denoted CPP3) were significantly (P < 0.05) higher in periodontitis rats with PIA. Additionally, there was a trend towards increased pro-inflammatory and anti-inflammatory cytokine levels, and increased α-1-AGP levels in plasma from periodontitis-challenged PIA rats. Conclusions Pre-existence of periodontitis induced antibodies against citrullinated peptide derived from PPAD in rats with PIA. However, there were no differences in the development or severity of PIA between periodontitis challenged and periodontitis free rats.

The study aimed to evaluate osteogenic properties of hydroxyapatite (HA) scaffold combined with extracellular matrix (ECM) derived in vitro from rat primary calvarial osteoblasts or dermal fibroblasts. The cellular viability, and the ECM deposited onto synthetic HA microparticles were assessed by MTT, Glycosaminoglycan, and Hydroxyproline assays as well as immunohistochemistry and scanning electron microscopy after 21 days of culture. The decellularized HA-ECM constructs were implanted in critical-sized calvarial defects of Sprague-Dawley rats, followed by bone repair and local inflammatory response assessments by histomorphometry and immunohistochemistry at 12 weeks postoperatively. We demonstrated that HA supported cellular adhesion, growth, and ECM production in vitro , and the HA-ECM constructs significantly enhanced calvarial bone repair ( p  < 0.05, Mann–Whitney U -test), compared with HA alone, despite the significantly increased number of CD68 + macrophages, and foreign body giant cells ( p  < 0.05, Mann–Whitney U -test). Selective accumulation of bone sialoprotein, osteopontin, and periostin was observed at the tissue–HA interfaces. In conclusion, in vitro -derived ECM mimics the native bone matrix, enhances the osteogenic properties of the HA microparticles, and might modulate the local inflammatory response in a bone repair-favorable way. Our findings highlight the ability to produce functional HA-ECM constructs for bone tissue engineering applications.

Background: Porphyromonas gingivalis (P.g) is unique among pathogens due to its ability to generate citrullinated proteins in an inflammatory milieu, potentially mediating the loss of immune tolerance, the production of anticitrullinated protein antibodies (ACPAs), and subsequently the development of rheumatoid arthritis (RA). Based on this hypothesis, we set out to investigate whether P.g is linked to ACPAs in a well-characterized German population. Participants and methods: A total of 600 participants (292 women and 308 men with a mean age of 67 years) of the European Prospective Investigation into Cancer and Nutrition-Potsdam study were selected in 2013, and paired saliva and serum samples were collected. Salivary P.g DNA and serum anticyclic citrullinated peptide (anti-CCP2) levels were quantified by real-time polymerase chain reaction and anti-CCP2 enzyme-linked immunosorbent assay, respectively. In selected participants, additional ACPA fine-specificities were also analysed on a custom-made multiplex peptide array. Results: Among participants with C-reactive protein greater than 3.0 mg/l, a one-unit increase in P.g DNA was associated with an almost twofold increase in anti-CCP2 levels. Moreover, participants with high P.g DNA had on average approximately 2.8-times higher anti-CCP2 levels when compared with participants with low P.g DNA, (Holm-adjusted p value = 0.01). Furthermore, citrullinated epitopes on α-enolase and vimentin were common ACPA reactivities among participants who also had high P.g DNA and elevated C-reactive protein. Conclusions: Our study suggests that in specific subgroups of individuals with systemic inflammation, higher salivary P.g DNA is associated with elevated serum ACPA. These data support a role for P.g in the development of anticitrulline immunity.

Background: Porphyromonas gingivalis (P.g) is unique among pathogens due to its ability to generate citrullinated proteins in an inflammatory milieu, potentially mediating the loss of immune tolerance, the production of anticitrullinated protein antibodies (ACPAs), and subsequently the development of rheumatoid arthritis (RA). Based on this hypothesis, we set out to investigate whether P.g is linked to ACPAs in a well-characterized German population. Participants and methods: A total of 600 participants (292 women and 308 men with a mean age of 67 years) of the European Prospective Investigation into Cancer and Nutrition-Potsdam study were selected in 2013, and paired saliva and serum samples were collected. Salivary P.g DNA and serum anticyclic citrullinated peptide (anti-CCP2) levels were quantified by real-time polymerase chain reaction and anti-CCP2 enzyme-linked immunosorbent assay, respectively. In selected participants, additional ACPA fine-specificities were also analysed on a custom-made multiplex peptide array. Results: Among participants with C-reactive protein greater than 3.0 mg/l, a one-unit increase in P.g DNA was associated with an almost twofold increase in anti-CCP2 levels. Moreover, participants with high P.g DNA had on average approximately 2.8-times higher anti-CCP2 levels when compared with participants with low P.g DNA, (Holm-adjusted p value = 0.01). Furthermore, citrullinated epitopes on α-enolase and vimentin were common ACPA reactivities among participants who also had high P.g DNA and elevated C-reactive protein. Conclusions: Our study suggests that in specific subgroups of individuals with systemic inflammation, higher salivary P.g DNA is associated with elevated serum ACPA. These data support a role for P.g in the development of anticitrulline immunity.

The repair of bone defects and nonunions remains a significant clinical problem in orthopedic and maxillofacial reconstructive surgery. Tissue engineering offers a potential approach to overcome existing limitations related to auto- and allograft tissues. Novel biomimetic engineering strategies enable us to model the desirable physiological signaling in the bioengineered devices and to study tissue repair and regeneration under conditions resembling the human in vivo context. In the current thesis we aimed to better understand how a biomimetic approach in tissue engineering could be applied towards the repair and regeneration of bone tissue in the craniofacial area. In our first study we designed a biomimetic construct composed of ceramic scaffold modified with in vitro-derived extracellular matrix (HA-ECM), and assessed the osteogenic properties of the generated HA-ECM in vivo. Cell-derived matrix enhanced the osteogenic properties of ceramic scaffold, and the construct modulated the local inflammatory response in a bone repair-favorable way. We then continued to investigate the osteogenic properties of bone marrow stromal cell (BMSC)-loaded constructs and assessed the cellular components of the elicited foreign body reaction following implantation. The implications of BMSCs in the regulation of the foreign body reaction triggered by the tissue-engineered constructs were highlighted, demonstrating higher efficiency for the BMSC combination therapy. Furthermore, we investigated the effect of HA-ECM on the osteogenic differentiation of periodontal ligament progenitor cells (PDLC) and assessed the effect of PDLC-seeded HA-ECM on the bone repair. The HA-ECM enhanced the osteogenic differentiation of PDLC and the treatment with PDLC- seeded HA-ECM significantly improved calvarial bone repair. In the final study we have been able to implement a GMP-grade methodology for the biomimetic construct production under complete xeno-free conditions. The resulted tissue- engineered construct has promoted osteogenic differentiation of human MSCs in vitro and displayed biological safety and high biocompatibility in vivo. In conclusion, the work presented in this thesis highlights the functional in vitro-generated biomimetic tissue-engineered constructs with enhanced osteogenicity, biocompatibility and suitable handling properties, as a promising tool for craniofacial bone regeneration.

Background Evaluating social vulnerability is a challenging task. Indeed, former studies demonstrated an association between geographical social deprivation indicators, administrative indicators, and poor pregnancy outcomes. Objective To evaluate the association between social vulnerability profiles, prenatal care use (PCU) and poor pregnancy outcomes (Preterm birth (PTB: <37 gestational weeks (GW)), small for gestational age (SGA), stillbirth, medical abortion, and late miscarriage). Methods Retrospective single center study between January 2020 and December 2021. A total of 7643 women who delivered a singleton after 14 GW in a tertiary care maternity unit were included. Multiple component analysis (MCA) was used to assess the associations between the following social vulnerabilities: social isolation, poor or insecure housing conditions, not work-related household income, absence of standard health insurance, recent immigration, linguistic barrier, history of violence, severe dependency, psychologic vulnerability, addictions, and psychiatric disease. Hierarchical clustering on principal component (HCPC) from the MCA was used to classify patients into similar social vulnerability profiles. Associations between social vulnerability profiles and poor pregnancy outcomes were tested using multiple logistic regression or Poisson regression when appropriate. Results The HCPC analysis revealed 5 different social vulnerability profiles. Profile 1 included the lowest rates of vulnerability and was used as a reference. After adjustment for maternal characteristics and medical factors, profiles 2 to 5 were independently associated with inadequate PCU (highest risk for profile 5, aOR = 3.14, 95%CI[2.33–4.18]), PTB (highest risk for profile 2, aOR = 4.64, 95%CI[3.80–5.66]) and SGA status (highest risk for profile 5, aOR = 1.60, 95%CI[1.20–2.10]). Profile 2 was the only profile associated with late miscarriage (adjusted incidence rate ratio (aIRR) = 7.39, 95%CI[4.17–13.19]). Profiles 2 and 4 were independently associated with stillbirth (highest association for profile 2 (aIRR = 10.9, 95%CI[6.11–19.99]) and medical abortion (highest association for profile 2 (aIRR = 12.65, 95%CI[5.96–28.49]). Conclusions This study unveiled 5 clinically relevant social vulnerability profiles with different risk levels of inadequate PCU and poor pregnancy outcomes. A personalized patient management according to their profile could offer better pregnancy management and reduce adverse outcomes.

Background Social deprivation is a major risk factor of adverse pregnancy outcomes. Yet, there is few studies evaluating interventions aiming at reducing the impact of social vulnerability on pregnancy outcomes. Objective To compare pregnancy outcomes between patients that received personalized pregnancy follow-up (PPFU) to address social vulnerability versus standard care. Methods Retrospective comparative cohort in a single institution between 2020 and 2021. A total of 3958 women with social vulnerability that delivered a singleton after 14 gestational weeks were included, within which 686 patients had a PPFU. Social vulnerability was defined by the presence of at least one of the following characteristics: social isolation, poor or insecure housing conditions, no work-related household income, and absence of standard health insurance (these four variables were combined as a social deprivation index (SDI)), recent immigration (< 12 month), interpersonal violence during pregnancy, being handicaped or minor, addiction during pregnancy. Maternal characteristics and pregnancy outcomes were compared between patients that received PPFU versus standard care. The associations between poor pregnancy outcomes (premature birth before 37 gestational weeks (GW), premature birth before 34 GW, small for gestational age (SGA) and PPFU were tested using multivariate logistic regression and propensity score matching. Results After adjustment on SDI, maternal age, parity, body mass index, maternal origin and both high medical and obstetrical risk level before pregnancy, PPFU was an independent protective factor of premature birth before 37 gestational weeks (GW) (aOR = 0.63, 95%CI[0.46–0.86]). The result was similar for premature birth before 34 GW (aOR = 0.53, 95%CI [0.34–0.79]). There was no association between PPFU and SGA (aOR = 1.06, 95%CI [0.86 – 1.30]). Propensity score adjusted (PSa) OR for PPFU using the same variables unveiled similar results, PSaOR = 0.63, 95%CI[0.46–0.86] for premature birth before 37 GW, PSaOR = 0.52, 95%CI [0.34–0.78] for premature birth before 34 GW and PSaOR = 1.07, 95%CI [0.86 – 1.33] for SGA. Conclusions This work suggests that PPFU improves pregnancy outcomes and emphasizes that the detection of social vulnerability during pregnancy is a major health issue.

1. Dry matter digestibility is a critical component of herbage nutritive value, a major service delivered by grasslands. The aim of this study was to test whether the dominance hypothesis applies to assess the impacts of environmental gradients and management regimes on thiscomponent of herbage nutritive value in permanent grasslands. 2. At the plant level, digestibility has been related to a number of functional traits, but whether this can be scaled up to the community level in species-rich grasslands and how such relationships are modulated by environmental conditions and management regimes remainunknown. Our primary objective was to test whether community-weighted means – species trait values weighted by the species abundance – of morphological, phenological and chemical traits could be used to explain variations in digestibility over a large range of climatic contexts,soil resource levels and management regimes. Our second objective was to explain variations in community digestibility within and among nine contrasting sites along large natural and man-induced environmental gradients.3. Over the whole data set, digestibility and most community-weighted means of traits responded to climatic factors and management regimes, but relations were not always significant when each site was considered separately. Community digestibility was significantly related to one or more plant traits within each site and to all of the measured traits when considering all the sites. Leaf dry matter content (LDMC) had the most consistent effects on digestibility, with a strikingly similar negative effect within each site. Potential evapotranspiration was negatively related to digestibility and contributed to explain a large part of the among-site variance. In addition, a low return interval of disturbance and a high disturbance intensity (biomass removal) were both associated with a high digestibility.4. Synthesis and applications. Disturbance regime, plant traits and local climate impacted dry matter digestibility roughly equally in grasslands. The effects of community composition on digestibility and its response to abiotic factors could be successfully captured by community weightedmeans of leaf dry matter content. This functional marker can be used to develop indicators and grassland management rules to support farmers in the refinement of their practices towards specific needs, such as target production outputs.